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Pharmacogenetics of Alcohol: Treatment Implications

This study has been completed.
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Jonathan Covault, University of Connecticut Health Center
ClinicalTrials.gov Identifier:
NCT00734656
First received: July 31, 2008
Last updated: March 26, 2012
Last verified: March 2012
  Purpose

This study will explore the hypothesis that effects of alcohol are in part mediated by increased production of neuroactive steroids, which interact with GABAA-receptors. We propose to study non-dependent drinkers using a 4-session within-subjects design in which alcohol / placebo is paired with dutasteride / placebo pretreatment. Dutasteride is a 5-alpha steroid reductase (5AR) inhibitor that limits the production of dihydrotestosterone and the 5a-reduced neuroactive steroids allopregnanolone, pregnanolone and 3a,5a-androstanediol.


Condition Intervention
Alcohol Related Disorders
Alcoholism
Alcohol Abuse
Drug: dutasteride + ethanol
Drug: placebo medication + ethanol
Drug: dutasteride + placebo alcohol
Drug: placebo medication + placebo alcohol

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Official Title: Subjective and Physiological Effects of Alcohol: Role of Genetic Variation and Adrenal Hormones

Resource links provided by NLM:


Further study details as provided by University of Connecticut Health Center:

Primary Outcome Measures:
  • Breath Alcohol [ Time Frame: 40 minutes after beginning drink ] [ Designated as safety issue: No ]
    Breath Alcohol level

  • BAES Sedation Response, Average of 6 Time Points [ Time Frame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking ] [ Designated as safety issue: No ]
    Biphasic Alcohol Effects Scale (BAES) Sedation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 sedation related questions regarding effects of alcohol. Total BAES sedation subscale score 0-70 with higher numbers indicating greater sedative effects of alcohol. [Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.]

  • BAES Stimulation Response, Average of 6 Time Points [ Time Frame: 40, 80, 120, 160, 210 and 240 minutes after start of drinking ] [ Designated as safety issue: No ]
    Biphasic Alcohol Effects Scale (BAES)Simulation items - sum of subjective responses - 0(not at all)to 10 (extremely)- for 7 stimulation related questions regarding effects of alcohol. Total BAES stimulation subscale score 0-70 with higher numbers indicating greater stimulating effects of alcohol. [Martin, C. S., M. Earleywine, R. E. Musty, M. W. Perrine and R. M. Swift (1993a). Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res 17(1): 140-6.]


Secondary Outcome Measures:
  • Change in Serum 3a-androstanediol Glucuronide [ Time Frame: Baseline (pre medication administration) and 2-4 days post-medication (alcohol session) ] [ Designated as safety issue: No ]
    Ratio of serum 3a-androstanediol drawn prior to alcohol administration (2-4 days after medication administration) compared to the baseline level prior to medication dose. The pharmacologic effect of dutasteride was measured by assay of serum 5a-androstan-3a,17b-diol,17-glucuronide (aka 3a-androstanediol glucuronide) as a biochemical measure of 5a-reductase enzyme inhibition. 3a-androstanediol glucuronide is the primary metabolic excretion product of 3a,5a-androstane neuroactive steroids. The


Enrollment: 94
Study Start Date: March 2007
Study Completion Date: July 2011
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo medication + placebo alcohol Drug: placebo medication + placebo alcohol
placebo medication administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
Experimental: Placebo Medication + 0.8 gr/kg Ethanol Drug: placebo medication + ethanol
placebo medication administered 2-4 days prior to ingestion of 0.8 gr/kg ethanol divided between three drinks consumed over 36 minutes
Experimental: 4 mg Dutasteride + Placebo Alcohol Drug: dutasteride + placebo alcohol
4 mg dutasteride administered 2-4 days prior to ingestion of three drinks each containing 1 cc ethanol consumed over 36 minutes
Other Name: Avodart
Experimental: 4 mg Dutasteride + 0.8 gr/kg Ethanol Drug: dutasteride + ethanol
4 mg dutasteride administered 2-4 days prior to ingestion of 0.8 mg/kg ethanol divided between three drinks consumed over 36 minutes
Other Name: Avodart

Detailed Description:

Alcohol has multiple pharmacological effects, though which of these effects relate to the risk of alcohol dependence is not clear. Animal studies indicate that the neuroactive steroid allopregnanolone is an alcohol-modulated endogenous agonist at GABAA receptors and that genetic variation in steroid 5a-reductase type I gene which generates neuroactive steroids, may moderate alcohol effects. To better define the role of neuroactive steroids we will conduct a laboratory study of non-alcohol dependent drinkers using a 4-session design in which alcohol/placebo beverage is paired with dutasteride/placebo pretreatment. Dutasteride, an inhibitor of both type I and type II 5a-reductase enzymes, blocks the production of 5a-reduced neuroactive steroids. This study will extend our preliminary findings with finasteride by including a) a placebo control for alcohol, b) a more specific inhibitor of both 5a-reductase isoenzymes, c) a larger group of subjects (including both light and heavy drinkers).

  Eligibility

Ages Eligible for Study:   21 Years to 45 Years
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Main Study: Subjects will be healthy volunteers with or without parental history of alcoholism who are 21-45 years old and who have a BMI >18.5 and <32.5. Drinking history: All subjects must report at least one occasion in the prior month of drinking at least 3 drinks on a single day; additionally, LD subjects will be selected if they drink 1-3 drinks, 1-3 times per week (up to 5 drinks per week on average), with no more than one occasion in the past 2 months on which they drank >4 drinks. HD subjects will be selected if they report drinking at least 10 drinks per week, with at least one episode per week of heavy drinking.

Exclusion Criteria:

  • Main Study: Subjects cannot have a current or past DSM-IV diagnosis of alcohol or drug dependence, current or past 24-months diagnosis of alcohol or drug abuse or another major psychiatric disorder, neurological illness, have had a hypersensitivity reaction to dutasteride, evidence of liver dysfunction, currently be using benzodiazepines, other psychotropic medications or medications that are known to influence steroid hormone levels or metabolism or modify the effects of alcohol. Nicotine-dependent subjects will be excluded to avoid the confounding effects of nicotine withdrawal during day-long laboratory sessions. Women are not allowed to participate. Subjects anticipating moving from the area during the period of their planned study participation will be excluded from study entry.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00734656

Locations
United States, Connecticut
University of Connecticut Health Center
Farmington, Connecticut, United States, 06030
Sponsors and Collaborators
University of Connecticut Health Center
Investigators
Principal Investigator: Jonathan Covault, MD, PhD University of Connecticut Health Center
  More Information

No publications provided

Responsible Party: Jonathan Covault, Associate Professor, University of Connecticut Health Center
ClinicalTrials.gov Identifier: NCT00734656     History of Changes
Other Study ID Numbers: 06-218S-2, 619, 5R01AA015606-02
Study First Received: July 31, 2008
Results First Received: October 27, 2011
Last Updated: March 26, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Connecticut Health Center:
steroid 5Alpha Reductase
dutasteride
neuroactive steroid

Additional relevant MeSH terms:
Alcohol-Related Disorders
Alcoholism
Chemically-Induced Disorders
Mental Disorders
Substance-Related Disorders
Dutasteride
Ethanol
5-alpha Reductase Inhibitors
Anti-Infective Agents
Anti-Infective Agents, Local
Central Nervous System Agents
Central Nervous System Depressants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses
Urological Agents

ClinicalTrials.gov processed this record on November 27, 2014